Table of Contents +lt;file0+gt; 2. ANTIANGINAL DRUGS BG Katzung + K Chatterjee I. General

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Table of Contents 2. ANTIANGINAL DRUGS BG Katzung & K Chatterjee 旼컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴 I. General aspects of drug treatment of angina 1. Mechanisms of action 2. Indications for antianginal drugs II. Nitrates 1. Properties 2. Adverse effects, toxicity 3. Table of drugs: III. Calcium channel blockers 1. Properties 2. Adverse effects, toxicity 3. Table of drugs IV. Beta-adrenoceptor blockers 1. Properties 2. Adverse effects, toxicity 3. Table of drugs 읕컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴컴 (PgDn key for more text) I. GENERAL ASPECTS OF DRUG TREATMENT OF ANGINA Three major drug groups are used in the treatment of angina: the nitrate vasodilators, the beta-adrenoceptor block- ers, and the calcium channel blockers. The nitrates and the cal- cium channel blockers are discussed in this chapter; the beta- blockers are described in detail in Chapter 5. Coronary artery bypass grafting and percutaneous transluminal coronary angioplasty are important reperfusion therapies that modify the need for pharmacologic therapy in suitable patients. Pathophysiology: Anginal pain is a symptom of inadequate oxygen delivery to the myocardium relative to the oxygen requirement of this tissue. This may be associated with: * Atherosclerosis, resulting in classic angina of effort or atherosclerotic angina; or * Vasospasm, resulting in vasospastic or Prinzmetal's variant angina; or * Unstable or crescendo angina: A rapid increase in frequency and intensity of anginal pain. It is thought to herald an im- minent myocardial infarction. (PgDn key for more text) Therapeutic Rationale * Increase oxygen delivery: This may be accomplished by surgery in the atherosclerotic form of angina or coronary vasodilators in the vasospastic form. * Reduce oxygen requirement by decreasing the work of the heart. This is especially important in the atherosclerotic form of angina but is useful in both types. It is achieved through the use of peripheral vasodilators that decrease arterial pressure and drugs that reduce cardiac output, either by an action directly on the heart, or by decreasing venous return. Mechanisms * Nitrates: The nitrates cause selective smooth muscle relaxa- tion, probably by release of the nitric oxide (NO) group, which apparently increases cGMP. There is little direct ef- fect on myocardial or skeletal muscle. In atherosclerotic angina, the major therapeutic mechanism is reduction of car- diac work by peripheral vasodilatation, especially of the veins. These drugs may also produce useful coronary vaso- dilatation in vasospastic and unstable angina, in which coronary vasospasm may be a major contributor to the relative ischemia of the tissue. (PgDn key for more text) * Beta-adrenoceptor blockers (see Chapter 5, ): Beta blockers decrease cardiac work by blocking 1 receptors in the myocardium and thereby decreasing cardiac output. They also reduce cardiac work by decreasing blood pressure. Although only 2 members of this group (both nonselective beta block- ers) have been approved for use in angina at the time of this writing, all beta-1 selective and nonselective beta blockers are effective in atherosclerotic angina. These drugs do not cause vasodilatation. * Calcium channel blockers: These agents directly cause peripheral vasodilatation and directly reduce cardiac work by reducing influx of activator calcium into smooth muscle and cardiac cells. In vasospastic and unstable angina, these drugs may cause a useful degree of coronary vasodilatation. (PgDn key for more text) References: 1. Symposium: Circulation 1985; 72 (Suppl V). 2. Takaro T et al: The Veterans Administration Cooperative Study of Stable Angina: Current status. Circulation 1982; 65 (Suppl 2): 60. 3. Gersh B J et al: Comparison of coronary artery bypass surgery and medical therapy in patients 65 years of age or older. N Engl J Med 1985;313:217. 4. Morse JR, Nesto RW: Double-blind crossover comparison of the antianginal effects of nifedipine and isosorbide dinitrate in patients with exertional angina receiving propranolol. J Am Coll Cardiol 1985; 6: 1395. (PgDn key for more text) II. NITRATES Pharmacokinetics (see also Table ) Drugs of Special Importance * Nitroglycerine is the prototype nitrate and available in many dosage forms. Substitutes are rarely needed. * Isosorbide dinitrate is the most popular substitute nitrate. * Nitrites, eg, amyl nitrite, are obsolete and should not be prescribed in angina. Amyl nitrite is still used as a temporary measure in the treatment of cyanide poisoning. Sodium nitrite is a more effective antidote for cyanide (see antidotes, Chapter 24). Several organic nitrites, including amyl and isobutyl nitrite, have been fad recreational drugs, supposedly providing "sex enhancement." Toxicity: Related Drugs: * Dipyridamole, not a nitrate compound, was promoted for use in angina. It is no longer labeled for this application. (PgDn key for more text) References: 1. Hoekenga D, Abrams J: Rational medical therapy for stable angina pectoris. Am J Med 1984; 76, 309. 2. Schneider WU et al: Dose-response relation of antianginal ac- tivity of isosorbide dinitrate. Am J Cardiol 1984; 53:700. 3. Scheidt S: Update on transdermal nitroglycerin: an overview. Am J Cardiol 1985; 56:3L 4. Thadani U et al: Transdermal nitroglycerin patches in angina pectoris. Dose titration, duration of effect, and rapid tolerance. Ann Int Med 1986; 105: 485. III. CALCIUM CHANNEL BLOCKERS CALCIUM CHANNEL BLOCKERS : PROPERTIES Three calcium channel blockers are presently available in the USA: diltiazem, nifedipine, and verapamil. Their major in- dication is in the treatment of angina. (PgDn key for more text) Pharmacokinetics (see Table ) Contraindications and Warnings References: 1. Johnson SM et al: A controlled trial of verapamil for Prinzmetal's variant angina. N Engl J Med 1981; 304: 862. 2. Lindenberg BS et al: Efficacy and safety of incremental doses of diltiazem for the treatment of stable angina pectoris. J Am Coll Cardiol 1983; 2:1129. 3. McAllister RG, Hamann SR, Blouin RA: Pharmacokinetics of calcium-entry blockers. Am J Cardiol 1985; 55:30B. 4. Muller JE et al: Nifedipine and conventional therapy for un- stable angina pectoris: a randomized, double-blind com- parison. Circulation 1984; 69: 728. 5. Weiner DA et al: Efficacy and safety of verapamil in patients with angina pectoris after 1 year of continuous, high-dose therapy. Am J Cardiol 1983; 51:1251. (PgDn key for more text) IV. BETA-BLOCKING DRUGS IN THE TREATMENT OF ANGINA Beta adrenoceptor antagonists are effective in preventing or reducing the incidence of attacks of angina of effort (see major indications above). They are not recommended for the man- agement of vasospastic angina. Their properties are discussed in detail in Chapter 5 . Although all of the "pure antagonist" -blockers appear to be equally effective in the prophylaxis of classic angina, only 2 (propranolol and nadolol) are presently labeled for this use (see Table ). References: 1. Alderman EL et al: Dose response effectiveness of propranolol for the treatmint of angina pectoris. Circulation 1975; 51: 964. 2. Thadani U et al: Comparison of the immediate effects of five B-adrenoceptor-blocking drugs with different ancillary properties in angina pectoris. N Engl J Med 1979; 300:750. (PgDn key for an additional reference) 3. Lynch P et al: Objective assessment of antianginal treatment: a double-blind comparison of propranolol. nifedipine, and their combination. Br Med J 1980;281: 184.

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